Familial hypercholesterolaemia (FH) is an autosomal co-dominant disorder that markedly raises plasma low-density lipoprotein-cholesterol (LDL-C) concentration, causing premature atherosclerotic coronary artery disease (CAD). FH has recently come under intense focus and, although there is general consensus in recent international guidelines regarding diagnosis and treatment, there is debate about the value of genetic studies. Genetic testing can be cost-effective as part of cascade screening in dedicated centres, but the full mutation spectrum responsible for FH has not been established in many populations, and its use in primary care is not at present logistically feasible. Whether using genetic testing or not, cholesterol screening of family members of index patients with an abnormally raised LDL-C must be used to determine the need for early treatment to prevent the development of CAD. The metabolic defects in FH extend beyond LDL, and may affect triacylglycerol-rich and high-density lipoproteins, lipoprotein(a) and oxidative stress. Achievement of the recommended targets for LDL-C with current treatments is difficult, but this may be resolved by new drug therapies. Lipoprotein apheresis remains an effective treatment for severe FH and, although expensive, it costs less than the two recently introduced orphan drugs (lomitapide and mipomersen) for homozygous FH. Recent advances in understanding of the biology of proprotein convertase subtilisin/kexin type 9 (PCSK9) have further elucidated the regulation of lipoprotein metabolism and led to new drugs for effectively treating hypercholesterolaemia in FH and related conditions, as well as for treating many patients with statin intolerance. The mechanisms of action of PCSK9 inhibitors on lipoprotein metabolism and atherosclerosis, as well as their impact on cardiovascular outcomes and cost-effectiveness, remain to be established.

INTRODUCTION

The causal relationship between hypercholesterolaemia resulting from elevation in plasma concentrations of low-density lipoprotein (LDL) and the development of atherosclerosis and coronary artery disease (CAD) is well attested by experimental, epidemiological and clinical trial evidence [1,2]. The critical importance of early and sustained lowering of elevated LDL to prevent the development of atherosclerotic disease has also recently been underscored by genetic association studies and Mendelian randomization analyses [3]. This is particularly relevant to the major form of autosomal dominant hypercholesterolaemia, commonly known as familial hypercholesterolaemia (FH).

FH is the most common monogenic disorder of lipid metabolism that leads to premature atherosclerotic CAD, but, in spite of major advances in scientific and clinical knowledge about the condition, most cases remain undetected or inadequately treated. FH is an autosomal co-dominant genetic disorder that impairs the catabolism of LDL particles by the liver, leading to severely elevated levels of LDL-cholesterol (LDL-C), which in turn can result in premature atherosclerotic disease, aortic stenosis and death [4]. Recent population data show that the heterozygous and homozygous forms of FH can affect 1 in 200 [5] and 1 in 300 000 people [6], respectively, using phenotypic and genotypic criteria. Diagnosis is based on a personal and family history, clinical presentation and the plasma lipoprotein profile [7]. Genetic testing is increasingly available to confirm the diagnosis. Although the traditional molecular understanding of FH was that it was due to critically sited mutations in the LDL receptor preventing the binding and internalization of LDL particles, further monogenic mutations have been found that cause a similar, usually less severe, phenotype [8,9]. Furthermore, hypercholesterolaemia due to multiple point mutations can cause a similar phenotype, and this may complicate cascade genetic screening [10]. We review recent advances in the assessment and care of FH, with a focus on the significance for the condition of the unique secretory protein proprotein convertase subtilisin/kexin type 9 (PCSK9).

INTERNATIONAL DEVELOPMENTS IN THE CARE OF FH

Several international guidelines, mostly based on expert opinion, have been published on the care of FH [1,2,8,9,11,12,14] (http://pathways.nice.org.uk/pathways/familial-hypercholesterolaemia). They generally agree about the methods of case detection and cascade screening, approaches to children and adolescents, lifestyle and drug treatment strategies, and indications for lipoprotein apheresis (LA).

Case detection, screening and diagnosis

In contrast to European and Australasian recommendations, the National Lipid Association in the U.S.A. recommends universal screening for hypercholesterolaemia in young people. Other recommendations suggest targeted screening of index cases in coronary care units and primary care, followed by cascade screening. FH in adults can be diagnosed using the Dutch Lipid Clinic Network, Simon Broome or MEDPED (Make Early Diagnosis to Prevent Early Deaths) criteria. The Dutch criteria may be the most sensitive for detecting FH and are preferred in Europe and Australasia [79], but the absence of details of family history or physical stigmata of FH decrease its specificity. Country-specific criteria validated against molecular diagnoses of FH are required to account for population differences in plasma LDL-C levels and FH-causing genetic mutations [9].

Genetic testing and cascade screening

European and Australasian approaches value genetic testing of families after detection of a pathogenic mutation in an index case with FH [9,15]. On one hand, it has been concluded that a combined phenotypic and genetic testing strategy offers the most effective approach for detecting new cases [8,9]. On the other hand, U.S. recommendations argue for cholesterol testing alone and do not at present see a role for genetic testing in FH screening. This is reasonable based on the wide mutation spectrum seen in FH in the U.S.A., the inability to identify pathogenic mutations in a significant proportion of people with phenotypically obvious FH, the currently high cost of DNA testing [12,16] and the complexity of care that a genetic screening programme generates [17]. Further complexity has been introduced with the recent recognition that phenotypic FH is not solely of monogenic origin but may, not uncommonly, be polygenic in origin [10,18]. This can substantially change the architecture and efficiency of a cascade screening strategy. However, advances in genetic testing and its inclusion in cascade screening will allow the detection of new mutations and become cheaper over time [1921]. Most cases of FH will be detected in primary care, where the use of genetic testing is not established and its application is at present not feasible [22,23]. A trial of the effectiveness of cascade screening using genetic, compared with cholesterol, testing is currently being conducted in the U.S.A. (D. Rader, personal communication). We recapitulate the issue of genetic testing in FH below.

Therapy and targets

A current treatment target for heterozygous patients is a 50% reduction in plasma LDL-C concentration. The 2011 guidelines of the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) suggest LDL-C targets of <2.5 mmol/l (<100 mg/dl) for patients without coronary heart disease (CHD) and <1.8 mmol/l (<70 mg/dl) for those with CHD; drawing on these guidelines, both the EAS and the International FH Foundation suggest LDL-C targets of <2.5 mmol/l (<100 mg/dl) for patients without CHD and <1.8 mmol/l (<70 mg/dl) for those with CHD or other major risk factors such as diabetes. Achieving these low targets can be difficult in FH with conventional therapy. Targets for children with heterozygous FH should be less intense than for adults, but currently there is a lack of evidence to support this. Most children who are heterozygous for FH will nevertheless require statin and other drug treatment, and LA should be considered in all children with homozygous FH [7,9].

Statins alone, or in combination with ezetimibe and possibly other agents, are the recommended treatment for meeting all LDL-C targets. The value of adding ezetimibe to a statin for cardiovascular events in high-risk patients was recently demonstrated in a large clinical trial (http://my.americanheart.org/professional/Sessions/ScientificSessions/ScienceNews/SS14-Late-Breaking-Clinical-Trials_UCM_468855_Article.jsp), al-though patients with FH were not specifically studied. Before initiating statin therapy, safety checks on liver and muscle enzymes are required, with regular monitoring of plasma aminotransferases and plasma creatine kinase if myalgia is reported. The safety of statins in children is reaffirmed by all guidelines, and their use is advised in patients with FH aged >10 years. Uniform recommendations are given for women with FH to avoid statins during (or when planning) pregnancy and lactation, and to choose low-oestrogen or progesterone-only oral contraceptives, with barrier methods preferred.

Integration of clinical service delivery: future challenges

The development and implementation of models of care for FH need to consider the integration of services, administrative and information technology requirements, auditing and research, clinical governance, teaching and training, practitioners acquiring credentials and establishing a family support group. Better integration and co-operation of specialist services with primary care are a substantial and worthwhile challenge to improve the currently suboptimal detection and treatment of patients with FH [22]. The biochemistry laboratory can effectively facilitate the detection and treatment of FH through its clinical liaison role with primary care [25], and partly automated notification systems for alerting the primary care physician to a possible case of FH, based on the plasma LDL-C criterion, could prove valuable [22]. The development and use of registries can play a significant role in enhancing care by, for example, facilitating clinical audits, clinical trials and health planning.

Implementation and sustainability of guidelines are the real challenges for health services. They require close collaboration of clinical, bureaucratic and political stakeholders to translate the evidence into government healthcare policy. As policy-making draws on the population's values and priorities, it is essential to raise community awareness about the benefits of early detection and treatment of FH.

Despite the many guidelines, there is currently no International Classification of Diseases (ICD) code for FH. The FH Foundation has recently submitted an application to address this major gap. The ICD code is required to accurately assess the incidence, complications, treatment and treatment outcomes of FH, with such data at present available only from local or national registries [6,2629]. Codification of FH and related conditions is essential to facilitate the standardization of the assessment of quality outcomes and organizational performance, as well as to provide enabling tools for research, healthcare financing and reimbursement strategies.

GENETICS OF FH

Gene variants

FH is most frequently caused by mutations of the LDLR gene, which encodes the LDL receptor. Less common than that caused by LDLR gene mutations, autosomal dominant hypercholesterolaemia with a similar phenotype to that of FH is caused by a defective APOB gene encoding an apolipoprotein-B100 (ApoB) molecule that does not bind normally to the LDL receptor and, even more rarely, by a gain-of-function mutation in PCSK9 [30]. LDLR mutations can be either receptor-defective, with 2–25% of normal LDL receptor activity, or receptor-negative or null, with <2% activity. The condition can be heterozygous, generally a less severe but more common form of FH in which there is only one FH-causing mutation, or, rarely, homozygous. Homozygosity can encompass true, or simple, homozygosity (identical mutations in each of the two FH-causing alleles), double heterozygosity (mutations of one allele each of two different genes, usually including an LDLR mutation and either an APOB or a PCSK9 mutation) and, most frequently, compound heterozygosity (a different mutation in each allele of the same gene) [30,31].

Whole exome and genome sequencing are likely to add to the more than 1600 already known mutations causing monogenic FH. FH diagnosed on clinical criteria, with no FH-causing genetic mutation being found, may frequently be caused by an accumulation of single nucleotide polymorphisms normally associated with a diagnosis of the more common so-called polygenic hypercholesterolaemia [10]. Conversely, ‘compensatory’ genes that lower LDL-C levels below diagnostic thresholds may make the diagnosis particularly difficult in children [32], leading to false reassurance that at-risk family members, who may be yet to express the FH phenotype, do not have FH based on a plasma cholesterol test alone. On the other hand, the natural history of younger people who are occasionally found to have a potentially pathogenic mutation but are normocholesterolaemic at the time of screening is unknown and requires further investigation. Non-pathogenic LDLR variants are, however, not associated with an increased frequency of CAD events [33]. Finally, the clinical phenotype of molecularly defined homozygous or compound heterozygous FH is quite variable [6], adding complexity to the use of genetic results in clarifying the disorder and moreover in determining the indications for use of the new therapies discussed below.

Prediction of CAD

The risk of CAD is variable in patients with FH and other risk factors such as hypertension, smoking and hyperlipoproteinaemia(a) play a role in determining the outcome in the individual patient, as may the contribution from any co-inherited polygenic hypercholesterolaemia [8,9]. The gene dosage effect, i.e. heterozygosity versus homozygosity, is the biggest determinant of clinical severity of the FH phenotype in terms of plasma LDL-C level and cardiovascular disease burden, but the type of mutation (receptor-defective or receptor-negative) causes significant variability within the heterozygous and homozygous groups in terms of plasma LDL-C levels and cardiovascular outcomes [34]. However, not all LDLR mutations are pathogenic, nor do they all accordingly increase the risk of CAD [33]. Genetic testing may therefore be useful in predicting the risk of atherosclerotic cardiovascular disease in FH, which varies widely, as has been shown with the LDL receptor-negative genotype [35,36] and variants in the ATP-binding cassette A1 (ABCA1) gene, which encodes a transporter that facilitates cholesterol efflux from macrophages to high-density lipoprotein (HDL) particles [37,38]. Associations between CAD and genetic variation of cyclin-dependent kinases that control cellular proliferation have also been described in FH [39]. The genetics of CAD risk in FH is complex and, beyond LDLR, no gene variants with a large effect size have so far been identified [40]. Hence, beyond simple knowledge of the family history of premature CAD and the coexisting plasma level of LDL-C, there is at present no genetic test that is useful in predicting risk of CAD in FH.

Prediction of the response to therapy

Mutation analysis also allows some prediction of the likely response to statins and other new drug therapies, as is discussed below, because the mechanism of action of these drugs depends on the functionality of the LDL receptor [41]. Response to drug therapy may also depend on the interaction with other genotypes, such as those relating to apolipoprotein E (ApoE), PCSK9, cholesteryl ester transfer protein (CETP) and P-glycoprotein drug transporter [4244]. Recent genome-wide association studies have confirmed that four loci–APOE, LPA, SORT1/CELSR2/PSRC1 and SLCO1B1–determine the response of LDL-C to statins [45], but their collective effect on the therapeutic responses in FH requires further investigation. The clinical application and cost-effectiveness of genetic testing in predicting the response to cholesterol-lowering therapy in the care of patients with FH also require further evaluation.

Clinical application: other inherited dyslipidaemias

Running counter to the case for genetic testing of the affected individual with a clinical FH phenotype and associated family members, an argument may be made that an individual with very high plasma levels of LDL-C is at high risk of cardiovascular disease in any case and genetic testing will not alter patient management. Genetic and pathophysiological delineation of the individual's disorder may allow some prediction of the response to particular therapies [36,37], but it may not substantially change the sequence of treatment decisions. False-negative results in mutation-negative patients with a clinical phenotype of FH, of whom there is probably a substantial proportion [46], could lead to a decision not to cascade screen families. Cascade screening using cholesterol testing alone may have a lower detection rate of new cases of FH than genetic testing [47], but a formal comparison of the yield, effectiveness, costs and acceptability of phenotypic and genotypic testing screening programmes is required. One such effort is under way in the U.S.A. (D. Rader, personal communication).

Whole exome sequencing has not been successful in identifying any significant new FH loci in mutation-negative clinically definite FH patients [48]. Screening for FH-causing mutations in individuals in the community with ostensible hypercholesterolaemia also gives an exceptionally low yield of <5% [49]. The ability to diagnose polygenic hypercholesterolaemia could potentially enhance genetic cascade screening for FH [10,18], but this requires further clinical testing and economic evaluation. The clinical dilemma is when a pathogenic mutation is not detected in a proband with phenotypically definite FH. As suggested by recent studies [10,18], this issue could be resolved by estimating an LDL-C gene score using six or 12 single nucleotide polymorphisms known to collectively have a significant cholesterol-raising effect [50]. Using this approach, at least half the patients thought to have mutation-negative FH could have polygenic hypercholesterolaemia [10]. In those individuals with probable polygenic hypercholesterolaemia, cascade screening using cholesterol testing alone could be restricted according to particular clinical circumstances, such as the prematurity of any family history of CAD. Conversely, in those determined by LDL-C gene score to have a low probability of polygenic hypercholesterolaemia, cascade screening, based on age- and gender-adjusted plasma LDL-C thresholds, may be recommended [7], whereas an extended molecular search for the ‘missing’ pathogenic mutation could be worthwhile. Polygenic hypercholesterolaemia could mimic heterozygous FH when associated with other inherited conditions that predispose to premature CAD [51].

Other inherited dyslipidaemias that need to be considered when grappling with the issue of mutation-negative FH include familial combined hyperlipidaemia [52], in which there is also a consistently high plasma concentration of ApoB and a family history of premature CAD, with coexistent insulin resistance and variable hypertriglyceridaemia. Another is inherited elevation in lipoprotein(a) [Lp(a)], an independent risk factor for CAD [53], which in the presence of cholesterol-raising alleles can mimic FH.

Genetic testing in FH, as in other medical conditions, needs to be applied with good clinical judgement and in the setting of a fully informed doctor–patient alliance. Families need to be counselled about risk communication and the implications of the results [7]. The additional services required for genetic testing are usually available via centralized systems of care in advanced centres in developed countries, but not in less developed countries or primary care settings, where screening for FH will have to rely on cholesterol testing alone. Further work is required to test the use and cost-effectiveness of the LDL-C gene score in real-life clinical settings and in racial groups other than white people [16]. Although all genetic results can refine the diagnosis of FH, knowledge of the plasma LDL-C, concomitant risk factors, and the presence of overt or subclinical CAD will continue to govern the therapy of FH and polygenic hypercholesterolaemia. Whatever the method of screening, the principle of counselling the genotype and treating the phenotype will continue to guide clinical practice [7].

METABOLIC BASES

Although suppressed hepatic uptake of LDL from plasma due to defective LDL receptors explains the markedly reduced fractional rate at which these lipoprotein particles are removed from plasma, the delivery of cholesterol to the liver is in fact greater than normal. In homozygous FH with at least one receptor-deficient LDLR mutation, the rate of non-receptor-mediated uptake of cholesterol by the liver is greater than in heterozygous FH. Accordingly, stable isotope tracer studies have shown increased ApoB secretion in patients with FH secondary to LDLR mutations, with receptor-negative mutations causing the highest hepatic secretion rates of ApoB [54]. A possible mechanism is that non-LDL receptor-mediated uptake of LDL-C into hepatocytes in FH increases intracellular cholesteryl ester (CE) concentrations, enhancing the hepatic secretion of ApoB [54]. This pathway may also operate in patients who do not have FH, highlighting one of the many aspects of cholesterol homoeostasis that is not yet well understood. Elevation of PCSK9 levels in FH may also contribute to increased hepatic secretion of ApoB and this requires further investigation [55,56].

Lp(a) is an LDL-like particle in which an apolipoprotein(a) [Apo(a)] moiety, which is under separate genetic control, is covalently adducted via disulfide bridges to LDL [57]. Being highly atherogenic and prothrombotic, elevated Lp(a) enhances CHD risk in FH [58]. Although structurally similar to LDL, Lp(a) is metabolized via different metabolic pathways that relate either to scavenger receptor-B1 (SR-B1) or to sorting and endocytic receptors [59], but these remain to be defined. Although Lp(a) is not thought to interact with the LDL receptor, plasma levels of Lp(a) are higher in patients with homozygous FH compared with heterozygous FH and non-FH patients [60], suggesting a possible role for the LDL receptor pathway in determining plasma levels of Lp(a). Elevated levels of Lp(a) are often seen in FH, as well as patients without FH in the absence of raised LDL-C levels. Plasma Lp(a) concentration is predominantly determined by genetic variation, principally related to the number of K-IV type 2 kringle repeats encoded by the LPA gene in FH and non-FH patients, but also appears to be independently associated with LDL receptor defects [58,60]. Lp(a) catabolism is not affected by FH, consistent with a lack of evidence of a role for the LDL receptor in its clearance; rather, an increase in Apo(a) secretion, in association with the increased ApoB secretion in FH and/or an increased coupling of Apo(a) with LDL ApoB, might occur [54].

TREATMENT OF FH

In addition to dietary and lifestyle advice and attention to other cardiovascular risk factors, the cornerstone of treatment in most patients with FH is lipid-lowering drug therapy with statins. The therapeutic efficacy of statins is dependent on LDL receptor function, and these agents are therefore less effective in LDL receptor-negative than in-receptor-defective homozygous FH [61]. Alone or in combination with other standard therapies (ezetimibe, bile acid sequestrants, fibrates, niacin), statins do not attain LDL-C targets in many patients with heterozygous FH and almost never in those with homozygous FH. The value of adding ezetimibe to a statin in patients at high risk for CAD events has recently been confirmed in a large outcome trial, with ezetimibe adding a 6.4% relative risk reduction in cardiovascular events when added to a statin (http://my.americanheart.org/professional/Sessions/ScientificSessions/ScienceNews/SS14-Late-Breaking-Clinical-Trials_UCM_468855_Article.jsp). With the exception of niacin, which lowers Lp(a) by about 25%, no standard therapies for FH substantially lower the plasma concentration of Lp(a). Aspirin may specifically lower Lp(a) by up to 20%, whereas newer therapies such as mipomersen, anacetrapib and the PCSK9 inhibitors non-specifically lower Lp(a) by up to 30%, and LA by 75% [59]. Lomitapide also lowers plasma Lp(a), but its effect may diminish in the longer term and, as with mipomersen, is approved only for homozygous FH [62].

Lipoprotein apheresis

LA refers to the selective removal of lipoproteins, particularly LDLs, by means of an extracorporeal circuit [63]. In addition to maximal tolerated pharmacotherapies, this is the current treatment of choice for homozygous FH and can be started in childhood [14]. Although small children may initially require therapeutic plasma exchange, as the extracorporeal plasma volume requirement for selective apheresis methods is usually greater, paediatric apheresis kits allowing smaller plasma volumes are now available [61]. LA is also indicated for adults with heterozygous FH who have not achieved the LDL-C targets and have progressive cardiovascular disease despite maximal tolerated drug therapy. LA may also be indicated for adults with elevated plasma levels of Lp(a), especially those with established CHD [61,64].

LDL-C is acutely lowered by more than 60% by LA and additional benefits include the lowering of triacylglycerol and Lp(a) levels. Regression of coronary and carotid atherosclerosis, measured by angiography and intravascular ultrasonography, has been demonstrated in several studies in patients with phenotypic FH and known CAD [6572]. Reductions in Lp(a) levels with apheresis may improve CHD outcomes independently of changes in LDL-C levels [73].

A recent study using [18F]fluorodeoxyglucose positron emission tomography showed that inflammation of the aorta and carotid arteries in patients with FH improved after 8 weeks of weekly LA [74]. The effect of apheresis on circulating inflammatory markers has been demonstrated previously [75]. Whether this relates to the direct removal of inflammatory substances or reduced cytokine expression remains unclear. Preliminary evidence from one of the authors (C.S.), using the method of direct adsorption of lipoproteins, suggests that both mechanisms may apply.

Summary

Expert opinion is generally congruent on the standards of care for FH, but international guidelines are divided on the present clinical value of genetic testing. Genetic testing enhances the accuracy of diagnosis and may be useful in predicting CAD risk and response to statins, but a significant proportion of patients with a frank clinical diagnosis are not found to have a mutation affecting the LDL clearance pathway. Coexisting polygenic hypercholesterolaemia in this setting may be suspected where there is a high ‘cholesterol gene’ score. The metabolic defects in FH extend beyond hypocatabolism of LDL and include elevations in triacylglycerol and Lp(a) levels. The cornerstone of therapy for heterozygous FH is a statin with or without ezetimibe, and LA for homozygous and other more severe forms of FH. LA has recently been shown to improve arterial inflammation.

PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9

Paradigm shift in understanding of lipid metabolism and therapy for FH

Experimental research and clinical research over the past decade have improved our understanding of lipoprotein metabolism beyond the key notions originally elucidated by Goldstein and Brown [76], particularly in relation to certain regulatory elements. One such element is a cell-surface regulatory protein called PCSK9, which exerts a profound effect by promoting degradation of the LDL receptor. This has given PCSK9 and methods of pharmacologically manipulating its activity an intense focus of research that is highly relevant to treatment of the dyslipidaemias. We now review contemporary aspects of the biology and therapeutic regulation of PCSK9 and its significance for patients with FH.

Effects of PCSK9 mutation

Autosomal dominant hypercholesterolaemia shown to be caused by missense gain-of-function mutation of the PCSK9 gene was first reported in a French family, in which 12 of 29 family members tested had the defective gene and approximately 2- to 3-fold higher plasma concentrations of LDL-C than their unaffected relatives [77]. A recent study of 1096 Japanese patients with FH, in whom the PCSK9 mutation may be a more common cause for FH than in European patients, demonstrated significantly lower plasma total cholesterol concentrations in patients with causative PCSK9 mutations than in those with LDLR mutations, in both the heterozygous and the homozygous groups [78].

Conversely, nonsense mutations causing loss of function of PCSK9 result in low plasma levels of LDL-C which confers substantial lowering of CHD risk compared with controls. Compound heterozygosity for PCSK9 loss-of-function mutations resulted in undetectable circulating plasma PCSK9 levels and an extremely low LDL-C level of 14 mg/dl (0.36 mmol/l) in a woman who was fertile and otherwise in good health [79]. In a study of 3363 African–American patients, the 2.6% with nonsense mutations in PCSK9 had 28% lower LDL-C levels and 88% lower cardiovascular risk over 15 years [80]. Of 9524 white patients in the same study, the 3.2% with PCSK9 mutations had 15% lower LDL-C levels and 47% lower cardiovascular risk. No adverse health outcomes are known to be associated with PCSK9 loss of function, in contrast with other heritable disorders causing low levels of LDL-C such as abetalipoproteinaemia and hypobetalipoproteinaemia, which can result in hepatic steatosis and dietary malabsorption problems [79].

Physiological actions of PCSK9

The only clearly defined role of PCSK9 is to interrupt LDL receptor recycling (Figure 1). It binds to the epidermal growth factor-like repeat domain of the LDL receptor, separate from the ApoB-binding site [81]. After the LDL receptor has been internalized, the attached PCSK9 prevents the LDL receptor from forming a closed conformation in the sorting lysosome, which results in the subsequent cleavage of the LDL receptor by an endosomal cysteine cathepsin, and further degradation [82]. This prevents recycling of the LDL receptor to the cell surface, so preventing cholesterol uptake from the circulation via the LDL receptor-mediated pathway, which results in increased clearance through less efficient alternative pathways, leading to markedly higher plasma levels of LDL and maintained or possibly enhanced return of cholesterol to the liver [83].

Illustration of LDL-C and PCSK9 metabolism, showing sites of action of lipoprotein-lowering drugs

Figure 1
Illustration of LDL-C and PCSK9 metabolism, showing sites of action of lipoprotein-lowering drugs

MTTP, microsomal triacylglycerol transfer protein; TG, triacylglycerol.

Figure 1
Illustration of LDL-C and PCSK9 metabolism, showing sites of action of lipoprotein-lowering drugs

MTTP, microsomal triacylglycerol transfer protein; TG, triacylglycerol.

More recent evidence suggests that PCSK9 may increase plasma LDL-C levels by additional unrelated mechanisms. In LDLR−/− mice, a model analogous to receptor-negative homozygous FH, production of triacylglycerol-rich lipoproteins increased when infused with human PCSK9, despite the absence of the LDL receptor [84]. In another study, long-term over-expression of PCSK9 in an Ldlr−/− mouse model resulted in increased plasma concentrations of ApoB, very-low-density lipoproteins (VLDL) and LDL [85]. In contrast to the clinical implications of these findings, two patients with receptor-negative homozygous FH, when treated with an anti-PCSK9 monoclonal antibody for 12 weeks, exhibited no reduction in plasma LDL-C concentration despite a 90% reduction in PCSK9 plasma levels [86]. Whether intracellular regulation of PCSK9 using an alternative mode of therapy is effective in these patients remains open to question, but appears unlikely, given the complete absence of LDL receptors in this type of homozygous FH and the fact that the PCSK9 intracellular pathway plays a minor role compared with the extracellular pathway in regulating the LDL receptor [87].

Synthesis, regulation and clearance of PCSK9

PCSK9 is expressed mainly in the liver but also in other tissues including the small intestine, pancreas and vascular smooth muscle [8890]. It is synthesized as a 72-kDa zymogen which undergoes autocatalytic processing in the endoplasmic reticulum and Golgi body, and is ultimately secreted as a 62-kDa mature protein [91]. Its synthesis is up-regulated by sterol-regulatory-element-binding protein-2 (SREBP-2), a transcription factor that regulates expression by binding to the sterol-regulatory element in the promoter region of the gene [92]. SREBP-2 also increases synthesis of LDL receptors [76]. It is activated by low intracellular cholesterol concentrations, and also increases cholesterol synthesis via the activation of genes encoding hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase and other key enzymes involved in cholesterol production. A cholesterol-rich diet fed to fasting mice suppressed PCSK9 and SREBP-2 expression [81]. Prolonged fasting in animals and humans, however, also causes a decrease in PCSK9 and probably SREBP-2 activity [93]. In addition in vivo evidence suggests a possible role for insulin in increasing the expression of PCSK9 [94].

PCSK9 circulates in plasma in three main forms [95]:

  1. The mature 62kDa monomeric protein: this is exclusively carried by LDL, probably through association with the ApoB moiety of LDL, and represents about a third of circulating PCSK9. LDL-bound PCSK9 has diminished LDL receptor-binding activity. It has been proposed that this is a regulatory mechanism by which higher plasma concentrations of LDLs result in a greater proportion of PCSK9 being LDL bound, thereby inhibiting PCSK9-mediated degradation of the LDL receptor [96].

  2. A self-associated multimeric form: self-association is facilitated by the catalytic domain of PCSK9. In vitro evidence suggests that self-associated dimers and trimers have enhanced LDL receptor-binding and -degrading activity compared with the monomer. A known gain-of-function mutant PCSK9 displayed greater self-association, supporting the hypothesis that PCSK9 multimers have greater activity in vivo [97].

  3. A 55-kDa furin-cleaved inactive fragment resulting from the removal of the prodomain of the 62-kDa protein: mutations in the mature PCSK9 protein have been associated with increased or decreased susceptibility to furin cleavage, leading to some of the PCSK9 loss-of-function and gain-of-function genotypes, causing hypocholesterolaemia and hypercholesterolaemia, respectively [91].

The major mechanism for clearance of PCSK9 from plasma is via the liver and involves its internalization with the LDL receptor, a process that appears to be independent of the binding of LDL to the LDL receptor [81,84].

Possible extrahepatic actions of PCSK9

PCSK9 is expressed in human atherosclerotic plaques and may induce inflammation, contribute to endothelial dysfunction, and adversely affect glucose and adipose tissue metabolism, as demonstrated in vitro and in animal studies. Some evidence suggests that PCSK9 may have a modulatory effect on epithelial sodium channels, although a clinically relevant effect on blood pressure in humans has not been found. PCSK9-knockdown mice demonstrate LDL receptor up-regulation in the pancreas with reduced insulin levels and impaired glucose tolerance. In mice, PCSK9 limits adipogenesis. However, inhibition of PCSK9 in humans has not been found to contribute to hepatic steatosis or central adiposity [98].

Association between plasma concentrations of PCSK9 and LDL-C: significance for FH

Plasma concentrations of PCSK9 are correlated directly with those of LDL-C in the general population, albeit only modestly. The correlation probably relates to the SREBP-mediated up-regulation of both cholesterol and PCSK9 synthesis, degradation of the LDL receptor by PCSK9 resulting in increased circulating LDL-C and the existence of a shared pathway for clearance from plasma [99]. However, PCSK9 concentrations vary widely in a healthy population [93], suggesting a role for multiple influences, including genetic, nutritional and hormonal factors.

PCSK9 and LDL-C levels correlate in untreated FH, but the ratio of total PCSK9 to LDL-C concentration is lower than in the general population [100]. Cameron et al. [100] found that, compared with patients with normal cholesterol, patients with heterozygous FH had 1.8-fold higher LDL-C but only 1.2-fold higher PCSK9 levels; in homozygous patients, the LDL-C level was 7.7-fold higher but that of PCSK9 only 2.5-fold higher. This disproportionality has been reported elsewhere in FH [55]. It could reflect the fact that the PCSK9-binding site on the LDL receptor is unaffected by the FH-causing LDLR mutation and PCSK9 is therefore cleared normally, whereas LDL-C is not (Figure 2) [101,102]. Despite this, plasma levels of PCSK9 were not significantly different between heterozygous patients with LDLR mutations preventing PCSK9 binding (n=15) and those with defective LDL receptors that could still bind PCSK9 (n=48). However, it is possible that, despite an LDLR mutation preventing PCSK9 binding, the normally functioning LDL receptors in a heterozygous patient could compensate by clearing PCSK9 at an increased rate. In addition, the very high levels of LDL-C seen in FH may have unanticipated effects on PCSK9 kinetics related to self-association, and association with ApoB- and furin-mediated inactivation.

Depiction of normal clearance of PCSK9 despite a defective LDL receptor

Figure 2
Depiction of normal clearance of PCSK9 despite a defective LDL receptor
Figure 2
Depiction of normal clearance of PCSK9 despite a defective LDL receptor

Statins and PCSK9 up-regulation

Statins inhibit HMG-CoA reductase, a rate-limiting enzyme of cholesterol synthesis, resulting in lowering of the intracellular cholesterol concentration (see Figure 1). The consequent increased activity of SREBP up-regulates LDLR, causing expression of greater numbers of LDL receptors, which clear LDL particles from the plasma [76]. By activating SREBP, statins also up-regulate the PCSK9 gene, increasing plasma levels of PCSK9, correlating inversely with the lowering of LDL-C levels [103105].

The dose-dependent increase in PCSK9 concentration has been proposed as a mechanism that attenuates the effectiveness of statins at higher doses [55], and that pharmacological inhibition of PCSK9 could create a synergistic LDL-C-lowering effect when combined with statins. A recent study of non-FH patients did not support this notion, with an increase in atorvastatin dose from 10 mg to 80 mg daily failing to further reduce plasma concentrations of LDL-C significantly in patients receiving the PCSK9 inhibitor alirocumab [106]. Similarly, a 12-week study comparing the effect of the PCSK9 inhibitor evolocumab on LDL-C concentrations in patients with primary hypercholesterolaemia or mixed dyslipidaemia, receiving moderate- or high-intensity statin therapy, found no significant difference in the percentage of LDL-C lowering between statin groups [107], a finding that was replicated in a separate 52-week study [108]. This suggests that PCSK9 inhibition does not in reality act synergistically with statin therapy [102], because there appears to be only a maximal up-regulation of LDL receptor activity with the combination of a statin and a PCSK9 inhibitor. PCSK9 up-regulation may also therefore not greatly contribute to the logarithmic linear dose–response seen with statins. Nevertheless, PCSK9 inhibition itself has a potent LDL-C-lowering effect in patients with both FH and non-FH hypercholesterolaemia.

LA and PCSK9 removal

Tavori et al. [95] recently demonstrated that, in six patients with severe phenotypic FH, PCSK9 was removed by a standard method of LA and dextran sulfate adsorption. Plasma PCSK9 levels were lowered acutely by 52% and returned to pre-treatment values before the next scheduled apheresis 2 weeks later. Approximately 80% of PCSK9 was removed from the LDL-bound fraction of plasma. It is interesting that an additional 48% of PCSK9 was removed from the ApoB-free plasma fraction, suggesting another mechanism for removal of PCSK9 by LA from that for just the removal of LDL-bound PCSK9. Most of the PCSK9 removed from the ApoB-free fraction was in the inactive furin-cleaved form, with very little of the multimeric form recovered.

Cameron et al. [100] also sought to determine the effects of LA on PCSK9 levels in four patients with homozygous FH with contradictory findings. Although the methodology was not robust, plasma PCSK9 levels were not significantly different after apheresis despite substantial LDL-C lowering.

Statins and LA

Statins provide significant additive LDL-C lowering when used together with LA in FH. The mechanism is via attenuation of the rate of LDL-C re-bound between treatments [109]. Although it could be hypothesized that the removal of PCSK9 by LA would enhance the effects of statins by counteracting statin-induced up-regulation of PCSK9 synthesis, there is no convincing evidence for this. In a study of seven patients with homozygous FH, reported in 1997, which did not measure PCSK9 levels, the addition of atorvastatin to LA resulted in a 31% additional lowering of LDL-C, both pre- and post-apheresis, compared with placebo [109]. This is broadly comparable with the average reduction in LDL-C levels of approximately 25% with statin monotherapy in patients with homozygous FH and residual LDL receptor function [110].

THERAPEUTIC INHIBITION OF PCSK9

Drugs that inhibit PCSK9 are in advanced stages of development, most prominently the monoclonal antibodies evolocumab (formerly AMG145) and alirocumab (REGN727). They are fully humanized monoclonal antibodies that bind to PCSK9, preventing its binding to the LDL receptor. Other experimental approaches include antisense oligonucleotides, small-molecule inhibitors and siRNAs [111,112].

Efficacy

PCSK9 inhibitors lower LDL-C levels by about 50–70% in patients with primary hypercholesterolaemia, mixed hyperlipidaemia and heterozygous FH who are taking statins with or without ezetimibe, an effect that has been shown to be durable for at least 12 months in the case of evolocumab (Table 1) [107,108,113115]. In patients with heterozygous FH, the type of mutation (receptor-defective or receptor-negative) does not appear to affect the response to treatment [116].

Table 1
Effects of PCSK9 inhibitors on lipoproteins in selected clinical trials

If more than one dose or frequency of investigative drug was used, the effects of the dose with the greatest effect on LDL-C levels are shown in the Table. Except where noted, most patients in the study continued on standard lipid-lowering therapy including statins. Where a placebo control group was included, percentage change given in the Table is against placebo; where there was no placebo control group, percentage change is against baseline.

DrugPublicationPatientsDuration (weeks)ApoB (%)LDL-C (%)Triacylglycerol (%)HDL-C (%)Lp(a) (%)
Evolocumab Raal et al., 2012 [114Heterozygous FH (n=168) 12 −43 −55 −10 +9.1 −27 
 Raal et al., 2014 [116Heterozygous FH (n=331) 12 −49.4 −61 −12 +9 −28 
 Stein et al., 2013 [86Homozygous FH (n=8) ≥24 −14.9* −16.5* NA NA −11.7* 
 Raal et al., 2015 [117Homozygous FH (n=50) 12 −23.1 −30.9 +0.3* −0.1* −11.8* 
  Two receptor-defective mutations (n=28)  −38.4 −46.9   −19.8* 
  One receptor-defective, one negative mutation (n=9)  −22.4 −24.5   −23.8 
  Two receptor-negative mutations (n=1)  +9.3     
 Koren et al., 2014 [134Pooled data of hypercholesterolaemic patients enrolled in several evolocumab studies (n=736) 52 −42.6 −52.1 −9 +9.1 −29.9 
 Blom et al., 2014 [108Hypercholesterolaemic patients (n=599) 52 −44.2* −59.3* −11.5* +5.4* −22.4* 
Alirocumab Stein et al., 2012 [113Heterozygous FH (n=77) 12 −50 −68 −17* +12.3 −23* 
 Roth et al., 2014 [118Hypercholesterolaemic patients (n=52); monotherapy 24 −36.7* −47* −11.9* +6.0* −16.7* 
 Robinson et al. 2015 [133High risk patients including heterozygous FH (n=1553) 24 −54 −61.9 −17.3 +4.6 −25.6 
DrugPublicationPatientsDuration (weeks)ApoB (%)LDL-C (%)Triacylglycerol (%)HDL-C (%)Lp(a) (%)
Evolocumab Raal et al., 2012 [114Heterozygous FH (n=168) 12 −43 −55 −10 +9.1 −27 
 Raal et al., 2014 [116Heterozygous FH (n=331) 12 −49.4 −61 −12 +9 −28 
 Stein et al., 2013 [86Homozygous FH (n=8) ≥24 −14.9* −16.5* NA NA −11.7* 
 Raal et al., 2015 [117Homozygous FH (n=50) 12 −23.1 −30.9 +0.3* −0.1* −11.8* 
  Two receptor-defective mutations (n=28)  −38.4 −46.9   −19.8* 
  One receptor-defective, one negative mutation (n=9)  −22.4 −24.5   −23.8 
  Two receptor-negative mutations (n=1)  +9.3     
 Koren et al., 2014 [134Pooled data of hypercholesterolaemic patients enrolled in several evolocumab studies (n=736) 52 −42.6 −52.1 −9 +9.1 −29.9 
 Blom et al., 2014 [108Hypercholesterolaemic patients (n=599) 52 −44.2* −59.3* −11.5* +5.4* −22.4* 
Alirocumab Stein et al., 2012 [113Heterozygous FH (n=77) 12 −50 −68 −17* +12.3 −23* 
 Roth et al., 2014 [118Hypercholesterolaemic patients (n=52); monotherapy 24 −36.7* −47* −11.9* +6.0* −16.7* 
 Robinson et al. 2015 [133High risk patients including heterozygous FH (n=1553) 24 −54 −61.9 −17.3 +4.6 −25.6 

*P ≥ 0.05, not applicable or not provided. For all other values, P<0.05. NA, not available.

† Single-arm trial, or no patients randomized to placebo in subset analysis.

PCSK9 inhibition is unlikely to be as effective in homozygous FH, due to a lack of normally functioning LDL receptors. In particular, patients homozygous for receptor-negative mutations can be predicted to respond poorly. In a small trial of eight patients with homozygous FH, evolocumab lowered LDL-C by 26% in receptor-defective patients, and had no LDL-C-lowering effect in the two receptor-negative patients [86]. Subsequently, in a larger placebo-controlled trial, 33 patients with homozygous FH were allocated to evolocumab and 17 to placebo [117]. Patients who received evolocumab had a 30.9% lowering in LDL-C versus placebo. In post-hoc analyses, in patients with two defective mutations, LDL-C was lowered significantly by 46.9% versus placebo, and in those with one defective and one negative mutation by 24.5% versus placebo; the differences between these two groups was non-significant (P =  0.075). The one patient homozygous for receptor-negative mutations allocated to evolocumab did not respond to treatment. Overall, evolocumab did not significantly lower Lp(a), but in those with at least one defective LDL receptor it lowered it significantly by 25.1% (P =  0.005).

The mechanism by which PCSK9 inhibition lowers Lp(a) is unclear, given that Lp(a) is considered not to directly interact with the LDL receptor. The mechanism may, however, involve enhanced clearance of Lp(a) via a fully up-regulated LDL receptor, with correspondingly very low LDL/ApoB levels, or increased catabolism via alternative receptors, such as SR-B1 or endocytic receptors [59]. The role of the LDL receptor in the Lp(a)-lowering effect of evolocumab was underscored by the TESLA Part B study [117].

Adverse effects and immunogenicity

Evolocumab appears to be well tolerated, with similar rates of adverse events, including serious adverse events, between treatment and placebo arms of phase 3 and extended phase 2 studies at 12 months. No serious adverse events have been attributed to evolocumab, although longer-term safety data are needed. Adverse events appear to have led to higher discontinuation rates in evolocumab than placebo groups, largely due to injection site reactions, myalgias and various other symptoms, each reported in very few patients [108,115]. Although follow-up is only to 24 weeks, alirocumab appears to share a similar safety profile [118].

The detection of circulating antibodies that bind to anti-PCSK9 monoclonal antibodies in clinical trials has been described, but has not been associated with any adverse effects or with a loss of therapeutic effect [106,115].

Summary

PCSK9 is a unique protease that is critically involved in co-ordinating regulation of the LDL receptor pathway. Genetic association studies testify to its close relationship with CAD, with gain-of-function mutations mimicking an FH phenotype and loss-of-function mutations leading to a lifelong reduction in plasma levels of LDL-C, coupled with a reduction in CAD exceeding that seen in large statin trials. This has engendered the development of PCSK9 inhibitors as therapeutic agents, the most promising of which are monoclonal antibodies. Their profound LDL-C lowering and safety as monotherapy, and in combination with statins and ezetimibe, have been demonstrated in patients with several hypercholesterolaemias, including FH. The mechanism for the reduction in plasma Lp(a) levels seen with PCSK9 inhibitors remains unclear. PCSK9 inhibitors also decrease LDL-C concentrations in patients with homozygous FH with residual LDL receptor function. LA can also decrease plasma PCSK9 levels and this may contribute to the reduction in LDL-C in patients receiving this treatment.

OTHER NOVEL THERAPIES FOR HYPERCHOLESTEROLAEMIA

Apart from PCSK9 inhibitors, other new drugs with complementary modes of action are available on the market, or are in the pipeline, for the treatment of FH.

Microsomal triacylglycerol transfer protein inhibitors such as lomitapide inhibit the incorporation of CE and triacylglycerol into VLDLs and chylomicrons. In a single-arm, open-label, phase 3 study of 29 patients with homozygous FH, lomitapide in an intention-to-treat analysis lowered LDL-C levels by 40% at 26 weeks [62]. Plasma LDL-C concentrations fell to <2.6 mmol/l in eight patients. The significant reduction in LDL-C concentration was sustained at 78 weeks in 23 patients who completed the safety phase of the study. Three patients were able to discontinue LA, with a further three increasing the interval between LA treatments. Although gastrointestinal intolerance (diarrhoea, nausea, dyspepsia or abdominal discomfort) was very common, only three patients discontinued lomitapide. Of more concern, lomitapide resulted in elevation of aminotransferases and hepatic steatosis, the long-term significance of which is not yet clear. Theoretically, receptor-negative or receptor-defective status would not affect its efficacy. Lomitapide is approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of homozygous FH in the U.S.A. and Europe, respectively. The FDA requires that lomitapide carry a ‘black box warning’ about hepatotoxicity and that it be prescribed under a Risk Evaluation and Mitigation Strategy (REMS) programme [119].

Similarly, mipomersen, an antisense oligonucleotide that causes degradation of ApoB mRNA, thereby preventing synthesis of ApoB-containing lipoproteins, has been associated with an accumulation of hepatic fat. It lowers LDL-C levels by about 25–36% in patients with heterozygous and homozygous FH and, similarly to lomitapide, does not depend on functioning LDL receptors to work. Other than the potential for hepatotoxicity, mipomersen exhibits high rates of injection site intolerance and influenza-like symptoms [114,120122]. Mipomersen is FDA-approved for the treatment of homozygous FH, but was rejected by the EMA due to concerns relating to potential cardiovascular adverse effects. It also has an FDA-mandated ‘black box warning’ about hepatoxicity, and requires REMS programme participation for prescription [119]. The current annual costs per patient of both mipomersen and lomitapide are very high, being approximately 3- to 5-fold greater than the cost of LA.

Therapeutic inhibition of CETP, which transfers CEs from HDLs to the ApoB-containing lipoproteins in exchange for triacylglycerol, raises plasma levels of HDL-C by about 130% and decreases plasma levels of LDL-C by about 15–40% in patients with hypercholesterolaemia [123,124]. The newer CETP inhibitors, anacetrapib and evacetrapib, do not have the off-target adverse effect of torcetrapib on blood pressure [124] and are very well tolerated. As shown with anacetrapib, plasma concentrations of Lp(a) can also fall significantly by approximately 35%, but the mechanism for this remains to be investigated [123]. The potent CETP inhibitor evacetrapib also appears to enhance cellular cholesterol efflux (http://aha.scientificposters.com/epsAbstractAHA.cfm?id=14), which invokes a further cardioprotective mechanism beyond LDL-C reduction and elevation in HDL-C [126]. An interesting, off-target effect of CETP inhibition is the down-regulation of LDL receptor and PCSK9 expression via reduction of the active form of SREBP-2 [127]. In the REALIZE 52-week phase III study of patients with heterozygous FH, anacetrapib lowered plasma LDL-C by 39.7%. Four of the 203 patients randomised to receive anacetrapib experienced adverse cardiovascular events, compared with none of the 102 patients receiving placebo (p=0.15). Further outcomes data are awaited from suitably designed studies [128]. The CETP inhibitors are not yet approved for clinical use.

Role of new therapies in management of severe FH

For patients with heterozygous FH on LA, it is likely that the use of PCSK9 inhibitors will lead to a reduction in the frequency, or discontinuation, of apheresis as LDL-C targets are attained [129]. For patients with homozygous FH, the requirement for LA will probably persist, but the PCSK9 inhibitors, lomitapide or mipomersen may enhance the efficiency of apheresis; this may allow the treatment of smaller plasma volumes and/or for longer intervals between treatments. As PCSK9 inhibitors are likely to be substantially less expensive than LA, significant cost savings in treatment will accrue with heterozygotes, in whom these agents are likely to replace or reduce the need for LA. In the case of homozygous FH, lomitapide, which does not require any residual LDL receptor function to work, would probably be the more useful adjunct to apheresis. The use of mipomersen is limited by tolerability and potential adverse effects. The annual costs of both lomitapide and mipomersen are currently at least 3-fold greater than LA, and this needs to be considered when revising therapeutic strategies for severe FH. The efficacy and safety of CETP inhibitors in treating severe FH remain to be defined.

Most patients with homozygous FH due to receptor-negative mutations are likely to remain impossible to adequately treat pharmacologically without LA, but most homozygotes have at least one defective LDLR mutation and would be expected to respond to PCSK9 inhibitors. The high pre-treatment levels of LDL-C in severe FH mean that, safety concerns aside, ApoB anti-sense therapy is unlikely to be sufficiently efficacious in lowering LDL-C levels. It had been hoped that, as PCSK9 increases LDL-C levels in Ldlr−/− mice, LDL-receptor-independent mechanisms would allow PCSK9 inhibitors to work in the setting of receptor-negative homozygous FH. However, the present clinical trial evidence does not support this notion [86]. The efficacy and safety of the combination of lomitapide and a PCSK9 inhibitor in the management of severe FH, and its impact on the requirement for LA, await further investigation.

CONCLUSION

Recent developments in new therapies for hypercholesterolaemia have appositely redirected the attention of healthcare providers and researchers to the care of patients with FH. FH is more common than previously appreciated and provides a classic mandate for coronary prevention. Its detection and treatment are highly cost-effective [11,130]. Such recognition has spawned several international guidelines for detecting and managing FH. The role of DNA testing in clinical care has been questioned, particularly in the U.S.A. Genetic testing may enhance the efficiency of cascade screening and could have a future role in predicting CAD risk and response to drug therapy in FH, although in some settings the additional logistic complexity of genetic testing [131] could decrease overall efficiency when compared with a simpler phenotype-based strategy. Implementing guidelines and models of care for FH remain an international challenge and an ICD code for FH is a major priority.

New knowledge of lipoprotein metabolism, particularly the role of PCSK9, has led to the development of novel pharmacotherapies for FH. Anti-PCSK9 therapy is likely to provide a safe and effective option for lowering of LDL-C levels in most patients with FH, but cardiovascular outcomes data are awaited. In an analysis of open-label extension data from 12 phase II and III trials, patients allocated to receive evolocumab had a significant 53% relative risk reduction for cardiovascular events over 11.1 months. The trials incorporated into this analysis included patients at high risk for cardiovascular events including those with heterozygous FH, and statin intolerance [132]. A post hoc analysis of a randomised placebo-controlled trial of alirocumab, conducted over 78 weeks in patients at high risk for cardiovascular events, found a similar 48% relative risk reduction in the alirocumab group [133]. Patients with homozygous FH are likely to remain difficult to treat. None of the new cholesterol-lowering drugs is approved for use in children, in whom relevant studies are currently under way. Clarification of the mechanisms and consequences of the interactions between PCSK9 and its inhibition, statins and LA in patients with FH may provide fresh insights into future treatments. Further studies are required to assess whether PCSK9 inhibition and lomitapide can play a role in the management of children with homozygous FH. Potential benefits on the metabolism of postprandial triacylglycerol-rich lipoprotein require investigation. The mechanism for this effect of PCSK9 inhibitors and the interaction with apolipoprotein C-III (ApoC-III), as well as the effects on the assembly, secretion and catabolism of Lp(a) particles, are also important questions for future research.

If proven to be safe, efficacious and cost-effective in the long term, anti-PCSK9 monoclonal antibodies may, along with statins and ezetimibe, become the standard of care for many patients with severe forms of FH. This treatment may also apply to a wider spectrum of high-risk patients with polygenic hypercholesterolaemia [107], and as monotherapy or in combination with ezetimibe for patients with intolerance mainly due to statin myopathy [135]. However, beyond FH and statin-intolerant patients, the wider applications of anti-PCSK9 therapy, as additional therapy to statins [136], may depend on the results of large clinical outcome trials, such as ODYSSEY (NCT01663402) with alirocumab, FOURIER (NCT01764633) with evolocumab and SPIRE-1 and -2 (NCT01975389, NCT01975376) with bococizumab, which are currently being undertaken in individuals at high risk of cardiovascular disease.

Abbreviations

     
  • Apo(a)

    apolipoprotein(a)

  •  
  • ApoB

    apolipoprotein-B100

  •  
  • CAD

    coronary artery disease

  •  
  • CE

    cholesteryl ester

  •  
  • CETP

    cholesteryl ester transfer protein

  •  
  • CHD

    coronary heart disease

  •  
  • EAS

    European Atherosclerosis Society

  •  
  • EMA

    European Medicines Agency

  •  
  • FDA

    Food and Drug Administration

  •  
  • FH

    familial hypercholesterolaemia

  •  
  • HDL

    high-density lipoprotein

  •  
  • HMG-CoA

    hydroxymethylglutaryl-coenzyme A

  •  
  • ICD

    International Classification of Diseases

  •  
  • LA

    lipoprotein apheresis

  •  
  • LDL

    low-density lipoprotein

  •  
  • LDL-C

    low-density lipoprotein-cholesterol

  •  
  • Lp(a)

    lipoprotein(a)

  •  
  • PCSK9

    proprotein convertase subtilisin/kexin type 9

  •  
  • REMS

    Risk Evaluation and Mitigation Strategy

  •  
  • SR-B1

    scavenger receptor-B1

  •  
  • SREBP-2

    sterol-regulatory-element-binding protein-2

  •  
  • VLDL

    very-low-density lipoprotein

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Author notes

1

Gerald Watts has received honoraria for advisory boards and research grants from Sanofi and Amgen.